No Dysplasia Research Articles

Gastric metaplasia as a precursor of nonconventional dysplasia in inflammatory bowel disease

Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions.We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD.Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation.In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations.

422 Positive Association Between CDX2 and MUC2 Intestinal Factors and Dysplasia in Barrett’s Esophagus Utilizing WATS3D Tissue Sampling and Analysis

INTRODUCTION: During the pathogenesis of Barrett’s esophagus (BE), the background columnar epithelium often shows evidence of intestinal differentiation, such as early expression of intestinal specific transcription factors (CDX2) and late expression of mucin proteins (MUC2), prior to the development of goblet cells. The clinical significance of these markers is unknown. The aim of this study was to evaluate the association between the expression of CDX2 and MUC2, and the presence and grade of dysplasia in a large cohort of patients with endoscopic evidence of esophageal columnar mucosa using wide area transepithelial samples (WATS3D, CDx Diagnostics, Suffern, NY). METHODS: Over a 2-year period, we collected data from 129,158 consecutive patients with endoscopic evidence of esophageal salmon colored mucosa who were evaluated with WATS: 125,749 no dysplasia (ND), 2,012 crypt dysplasia (CD), 745 low grade dysplasia (LGD), and 652 high grade dysplasia/adenocarcinoma (HGD/EAC). CDX2 and MUC2 immunostaining was performed, and then their extent was graded semi-quantitatively (on a 4-point scale) in the background non-dysplastic, non-goblet epithelium, from all patients. The CDX2 and MUC2 results were then correlated statistically with the presence and grade of dysplasia. RESULTS: Table 1 summarizes the data according to dysplasia grade. Overall, 33.3% of cases were CDx2- MUC2-, 30.6% were CDx2+ MUC2-, and 36.1% were CDX2+ MUC2+. A significant (P &lt; 0.0001) increase in CDX2+ MUC2+ staining occurred in dysplasia cases (97.0%) compared to non- dysplasia cases (34.5%). Upon regression analysis, there was a highly significant (P &lt; 0.0001) association between both the presence and grade of CDX2 and MUC2 staining and dysplasia, that increased progressively from CD to LGD to HGD/EAC. CDX2+ MUC2+ was present, uniformly, in more than 94% of all dysplasia categories. In a sub-analysis of either CDX2 or MUC2 staining in ND vs. HGD/EAC cases only, there was a significant increase (P &lt; 0.0001) in the grade of CDX2, and in the grade of MUC2, staining, such that 3+ or 4+ CDX2 or MUC2 staining was noted in 8.8% and 9.1% of ND cases, respectively, compared to 54% and 41%, respectively, in HGD/EAC. CONCLUSION: CDX2 and/or MUC2 positivity is a highly significant risk factor for dysplasia/EAC in patients with endoscopic evidence of esophageal columnar mucosa. CDX2/MUC2 immunostaining may represent a more effective method of confirming Barrett’s esophagus, and the risk for dysplasia/cancer, than the identification of goblet cells.

136 Usefulness of Magnifying Narrow-Band Imaging Endoscopy for the Diagnosis of Sessile Serrated Adenoma/Polyp With Dysplasia/Carcinoma

INTRODUCTION: Sessile serrated adenoma/polyp (SSA/P) is an early precursor lesion in the serrated neoplasia pathway, which results in BRAF-mutated colorectal carcinomas with high levels of microsatellite instability. Therefore, accurate diagnosis of SSA/P and its dysplastic components is endoscopically important. However, the usefulness of magnifying narrow-band imaging (NBI) endoscopy for SSA/Ps with dysplastic change has not yet been fully elucidated. The aim of this study was to verify the usefulness of magnifying NBI endoscopy for the diagnosis of SSA/P with dysplasia/carcinoma. METHODS: Among 939 endoscopically or surgically resected lesions pathologically diagnosed as SSA/P with or without dysplasia/carcinoma at Juntendo University Hospital (Tokyo, Japan) between 2011 and 2018, a total of 709 lesions had images available. These SSA/P lesions included 647 with no dysplasia (ND), 37 with low-grade dysplasia (LGD), 15 with high-grade dysplasia (HGD), and 10 with submucosal invasive carcinoma (SIC). We retrospectively evaluated magnifying NBI endoscopic findings using the Japan NBI Expert Team (JNET) system. RESULTS: The clinicopathological and endoscopic characteristics of the studied lesions are summarized in Table 1. The HGD and SIC lesions were associated with advanced age. All the lesions were more frequently located in the proximal colon. The SIC lesions were significantly larger than the ND and LGD lesions. All the lesions frequently exhibited endoscopic findings characteristic of SSA/P, such as mucus cap and Type II-Open pit pattern. As for the JNET classification of magnifying NBI endoscopy findings, all 709 lesions were type 1. Six hundred and eighteen (96%) ND lesions exhibited type 1 only, whereas 52 (84%) SSA/P with dysplasia/carcinoma lesions had a combination of type 1 and types 2A, 2B, or 3, corresponding to SSA/P and dysplasia/carcinoma, respectively (Figures 1 and 2). Furthermore, the JNET classification had high sensitivity (84%) and specificity (96%) for diagnosing SSA/P with dysplasia/carcinoma. CONCLUSION: Recently, the JNET was established and has proposed a universal NBI magnifying endoscopic classification of colorectal tumors. Our findings suggest that the use of magnifying NBI endoscopy using the JNET classification might be useful for the diagnosis of not only conventional colorectal tumors, but also SSA/P with dysplasia/carcinoma. This increased awareness may also improve the recognition of SSA/Ps with dysplasia or invasive carcinoma.

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Does Multifocal Dysplasia in Barrett’s Esophagus Increase the Risk of Progression to Esophageal Adenocarcinoma?: Presidential Poster Award

Introduction: Barrett’s Esophagus (BE), is thought to be secondary to gastroesophageal reflux disease and progresses to esophageal adenocarcinoma (EAC) in a stepwise manner. Current guidelines utilize dysplasia to guide management, but there is conflicting evidence on the extent of dysplasia for risk stratification. Here, we evaluated the effect of multifocal dysplasia on the risk for EAC and hypothesized that multifocality in low-grade dysplasia (LGD) and high-grade dysplasia (HGD) are risk factors for progression to EAC. Methods: This was a retrospective study of BE patients with, or with suspected, dysplasia presenting to an academic medical center for evaluation from 2006 to 2016. Information collected include: patient demographics; BE length; histology, including grade and presence of multifocal dysplasia; disease progression; PPI use; need for esophagectomy; and length of follow-up. All pathology specimens were read by expert GI pathologists as: no dysplasia (ND), indefinite for dysplasia (IND), LGD, or HGD. LGD or HGD was further categorized as unifocal or multifocal. Results: Of 305 BE patients with, or with suspected, dysplasia, 51 were excluded (33 ND, 18 IND). 254 BE patients were included in the final analysis: 112 LGD (unifocal=90, multifocal=22) and 142 HGD (unifocal=108, multifocal=34). In total, twenty-five patients with dysplastic BE (13 unifocal, 12 multifocal) developed EAC; all were diagnosed with intramucosal adenocarcinoma with either T1a or T1b lesions. Multifocality significantly increased the risk for progression to EAC (Table 2: RR 3.26, p=0.004), with the effect most pronounced in the subgroup with multifocal LGD as compared to those with unifocal LGD (RR 8.18, p=0.013). In patients with HGD, multifocality did not increase the risk for subsequent EAC (RR 2.31, p=0.079). Lastly, multifocal dysplasia associated with long segment BE (LSBE) significantly increased the risk for EAC (Table 3: RR 3.09, p=0.011), and HGD patients with LSBE were more at-risk for progression to EAC than that of LGD patients (RR 4.33, p=0.007). Conclusion: Multifocal dysplasia significantly increases the risk of progressing from BE to EAC and is especially important in BE patients with LGD. Identification of the extent of dysplasia is also essential in patients with LSBE, particularly those diagnosed with HGD. If confirmed, incorporating dysplasia multifocality into the BE management algorithm should be considered.335_A Figure 1 No Caption available.335_B Figure 2 No Caption available.335_C Figure 3. Short Segment (SS) BE is defined as <3 cm in length, while Long Segment (LS) BE is defined as > or = to 3 cm in length

Long-term follow-up of patients with Barrett esophagus: Progression to high-grade dysplasia and esophageal adenocarcinoma according to histology at presentation.

20 Background: Esophageal adenocarcinoma (EAC) incidence is rising and prognosis is uniformly poor, even with early stage disease. Barrett esophagus (BE) serves as a premalignant marker for EAC, with an estimated progression of 0.5% per year. Low-grade (LGD) and high-grade dysplasia (HGD) confer a higher risk of progression, providing an opportunity for intervention and surveillance. Aims: To evaluate a large cohort of patients undergoing endoscopic evaluation of BE and thereby better understand the natural history of BE and dysplasia. Methods: A retrospective review of endoscopic databases was conducted for all patients with the diagnosis of BE undergoing upper endoscopy at a tertiary academic medical center from 1991-2010. All endoscopy and accompanying pathology reports were reviewed. Only those patients with 2 biopsies documenting specialized intestinal metaplasia were analyzed. Results: 848 patients underwent upper endoscopy for evaluation of BE. Of these, 674 patients met inclusion criteria, at a mean follow up of 66.6 months. Table 1 depicts the distribution of patients according to their histology at presentation. 22 (3.2%) patients presented with established EAC, while EAC developed in 51 (7.6%). Of patients with HGD, LGD, or no dysplasia (ND) at presentation, EAC ultimately developed in 30.6%, 6.6%, and 2.7%, respectively. EAC developed in 4 patients despite RFA treatment for ND (2) or LGD (2). HGD developed in 6 such patients after treatment for ND (3) and LGD (3). Only 1 patient in each RFA-treated cohort required esophagectomy, while the others cleared dysplasia or EAC with continuous treatment. Conclusions: In this large cohort of patients with Barrett’s esophagus, higher grade of dysplasia at first endoscopy was associated with development of EAC. Continuous surveillance during and after endoscopic treatment is necessary and often results in clearance of dysplasia and EAC. [Table: see text]

Surveillance in patients with long-segment Barrett's oesophagus: a cost-effectiveness analysis

ObjectiveSurveillance is recommended for Barrett's oesophagus (BO) to detect early oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the cost-effectiveness of surveillance.DesignWe included 714 patients with long-segment...

The patterns of reflux can affect regression of non-dysplastic and low-grade dysplastic Barrett's esophagus after medical and surgical treatment: a prospective case-control study.

To date, therapeutic guidelines and pattern of reflux for patients with no-dysplasia (ND) or low-grade dysplasia (LGD) Barrett's esophagus (BE) remain unclear. We aimed to analyze pattern of reflux and regression of ND- or LGD-BE after medical and surgical treatment. We studied a cohort of ND- and LGD-BE patients who underwent laparoscopic total fundoplication and a cohort of ND- and LGD-BE patients managed medically. Patients were matched for age, sex, and disease duration. After 1 year of follow-up at least, all patients underwent upper endoscopy with esophageal biopsies to evaluate any histological changes, as well as manometry and impedance-pH-metry to re-assess reflux patterns. Thirty-seven patients (20 LGD, 17 ND) undergoing laparoscopic fundoplication were enrolled and compared with 25 patients (13 LGD, 12 ND) managed with proton pump inhibitors (PPI). Laparoscopic fundoplication resulted in a better control of both acidic and weakly acidic reflux (P < 0.001) and was associated with a higher probability of reversion for LGD (P < 0.01). Esophageal motility did not differ between surgically and medically treated patients. In patients with ND- or LGD-BE, laparoscopic fundoplication seems to warrant a better control of all kinds of refluxate and it is associated with a higher likelihood of reversion of both LGD- and ND-BE, compared with PPI therapy.

PWE-104 Prevalance and significance of sessile serrated lesions from a large prospective UK series in the setting of bowel cancer screening programme

IntroductionScreening colonoscopy has not had a big impact in reducing right sided cancer mortality and it is believed that this could partly be due to sessile serrated lesions (SSLs) which...

319 Recurrence of Intestinal Metaplasia After Eradication of Barrett's Esophagus With Radio Frequency Ablation - Results From a BETRNet Consortium

Background: Although the incidence of esophageal adenocarcinoma (EAC) has increased by 500% over the past 40 years, the management of Barrett's esophagus (BE), a precursor to EAC, has remained largely ineffective and controversial. Current strategies employ endoscopic surveillance with biopsy to detect early cancer or high-grade dysplasia (HGD). The eradication of BE HGD with radiofrequency ablation (RFA) has demonstrated short-term efficacy in reducing the risk of progression to EAC. However, RFA for patients with non-dysplastic BE is controversial as a relatively small percentage of these patients progress to EAC. Recently published data demonstrated: 1) the need for multiple follow-up RFA treatments; and 2) lower progression rates from non-dysplastic BE to EAC than those previously published; these findings could significantly impact the decision to treat BE with no dysplasia (ND). The aim of our study was to analyze the effectiveness and cost-effectiveness of RFA for the management of BE, both with HGD and ND. Methods: A decision analytic Markov model was constructed. Separate analyses were conducted for cohorts consisting of HGD or ND BE patients. For the HGD analysis, we compared initial RFA to endoscopic surveillance with surgery when cancer was detected. For the ND analysis, we compared three strategies (S1,S2,S3): S1) endoscopic surveillance with surgery when cancer detected; S2) endoscopic surveillance with RFA when HGD detected; S3) initial RFA for ND followed by endoscopic surveillance. The simulation began with a hypothetical cohort of 50-year-old men with BE (HGD or ND) who were followed until age 80 or death. Age-related mortality, surgical mortality, EAC mortality and complications were modeled. In sensitivity analysis, three different rates of progression from BE ND to EAC were examined. Results: HGD ANALYSIS: Endoscopic surveillance was dominated by the Initial RFA strategy. ND ANALYSIS: S1 (Surveillance, Surgery for Ca) was dominated by the S2 (Surveillance, RFA HGD). When comparing S3 (Initial RFA) to S2 (Surveillance, RFA HGD), the incremental cost-effectiveness ratios (ICER) were $277,000, $140,000, and $109,000/Quality-Adjusted-Life-Year (QALY) using overall annual progression rates from ND to EAC of 0.12%, 0.33%, or 0.5% per year, respectively (Table 1). Sensitivity analysis on the progression rate from BE ND to EAC found that S3 (Initial RFA) could be cost-effective (assuming willingness to pay threshold=$100,000 per QALY) if EAC progression rates were greater than 0.6% per year. Conclusions: Using updated rates of cancer progression, our analysis found that for HGD the initial RFA strategy is both more effective and less costly than endoscopic surveillance. For BE ND, initial RFA is not cost-effective within the range of plausible progression rates of BE ND to EAC. Table 1

Tu1212 Prevalance and Significance of Sessile Serrated Lesions From a Large Prospective UK Series in the Setting of Bowel Cancer Screening Programme

Introduction Screening colonoscopy has not had a big impact in reducing right sided cancer mortality and it is believed that this could partly be due to sessile serrated lesions (SSLs) which are thought to be the precursors of microsatellite adenocarcinomas. In the UK, people from the age of 60 to 75 with positive faecal occult blood undergo screening colonoscopy. We aim to evaluate the prevalence and significance of SSLs in our screening population. Methods All colonoscopies performed between 2007 and 2011 were prospectively recorded on a screening database along with the histology. Pathology was reported as per standards laid out by the National screening programme by accredited Pathologists. Results We analysed 1948 polyps from a total of 1576 patients. 28/1948 polyps in 25/1576 patients were found to have sessile serrated lesions. This amounted to 1.4% of the total polyps found. Out of 25 patients, 13 patients were men. The prevalence of sessile serrated lesions in all patients with polyps was 1.7% 17/28 lesions. (60%) of the lesions were smaller than 10 mm. 17/28 (60%) were in the right colon. 14/28 (50%) had no dysplasia. 14/28 (50%) had low grade dysplasia. None had high grade dysplasia or cancer. No interval cancer was found in a mean follow-up of 12 months. All 25 patients with sessile serrated lesions were also found to have conventional adenomas. 1–2 adenomas were found in 6/25 patients, 3–4 adenomas in 6/25 patients and 13/25 patients had at least 5 adenomas. Prevalance of dysplasia: SSLs with dysplasia: 14/28 (50%) –Low grade dysplasia: 14/14, High grade dysplasia/cancer: 0/14 SSLs with NO dysplasia: 14/28 (50%). Conclusion (1) Our study shows a low prevalence of 1.7% of sessile serrated lesions accounting to Competing interests None declared.

Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study

Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett’s oesophagus

To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus.

Risk of malignant progression in patients with Barrett's oesophagus: a Dutch nationwide cohort study

BackgroundReported incidence rates of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus (BO) vary widely. As the effectiveness of BO surveillance is crucially dependent on this rate, its clarification is essential.MethodsTo estimate...

Progression to Colorectal Neoplasia in Ulcerative Colitis: Effect of Mesalamine

Some studies have suggested that mesalamine can prevent the development of colorectal cancer in patients with ulcerative colitis (UC). The aim of this study was to compare rates of progression with advanced neoplasia in patient cohorts with UC taking low and high doses of mesalamine and to determine where in the process of neoplastic progression mesalamine might act. Three cohorts of UC patients were identified from an institutional database: 311 patients with no dysplasia (NoD), 56 with indefinite dysplasia (IND), and 26 with flat low-grade dysplasia (fLGD). The impact of mesalamine exposure on the subsequent development of advanced neoplasia (high-grade dysplasia or colorectal cancer) was assessed using life-table methods. Seventeen of 311 patients with NoD progressed to advanced neoplasia (5-year rate, 1.1%). This rate was lower than the 5-year rate for the IND (9%; P = .02 vs NoD) and fLGD (45%; P < .001 vs NoD and P = .001 vs IND) cohorts. Among the NoD cohort, the hazard ratio for mesalamine users versus nonusers was 0.70 (95% confidence interval, 0.20-2.44), and for each 1 g/d increase in dose, the hazard ratio was 0.92 (95% confidence interval, 0.58-1.47). For patients with IND, no patients on greater than 2 g/d progressed versus 13.8% on low-dose mesalamine (P = .11). For fLGD, 62.5% on high dose progressed, versus 27.8% on low dose (P = .054). In long-standing UC, patients with fLGD have a higher rate of progression to advanced neoplasia than those with NoD or IND. However, at none of these stages of disease did mesalamine use show definitive chemopreventive activity.

Institutional and Comprehensive Review of Laryngeal Leukoplakia

The nature and interpretation of vocal fold leukoplakia has been limited by small study sizes. The present study reviewed institutional data and the published literature to better characterize vocal fold leukoplakia. At our institution, the histopathology, age, and malignant conversion rates of 136 patients (208 biopsies) with vocal fold leukoplakia from 1990 to 2005 were reviewed. No dysplasia (ND), mild and/or moderate dysplasia (MM), and severe dysplasia and/or squamous cell carcinoma in situ (SS) was identified in, respectively, 110 of 208 (53%), 38 of 208 (18%), and 31 of 208 (15%) biopsies. After 30 months (range, 1 to 134 months), malignant transformation was observed in 8 patients on subsequent biopsies. Additionally, a literature search was performed from 1960 to 2005 for the medical subject headings (MeSH) premalignant laryngeal lesions, laryngeal dysplasia, laryngeal leukoplakia, vocal cord dysplasia, and hyperkeratosis of the larynx. Fifteen reports were included for review. When these were combined with our institutional data, 1,173 of 2,188 biopsies (53.6%) revealed ND. Mild and/or moderate dysplasia and SS were present in 717 of 2,140 (33.5%) and 375 of 2,471 (15.2%) biopsies, respectively. Squamous cell carcinoma developed in 52 of 1,388 (3.7%), 83 of 824 (10.1%), and 56 of 310 (18.1%) patients whose initial biopsies demonstrated ND, MM, or SS. More than half of the reported leukoplakia lesions with biopsies showed ND. However, even lesions characterized as ND were associated with an increased risk of development of squamous cell carcinoma. Importantly, the risk of developing malignancy appears to correlate with the severity of dysplasia present on initial biopsy. Because clinical examination does not accurately predict the risk of malignancy, future studies, including genomic evaluation of this lesion, may be necessary to further characterize its biologic behavior.

Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists

To determine interobserver variation in grading of dysplasia in Barrett's oesophagus (BO) between non-expert general pathologists and expert gastrointestinal pathologists on the one hand and between expert pathologists on the other hand. In this prospective multicentre study, non-expert and expert pathologists graded biopsy specimens of 920 patients with endoscopic BO, which were blindly reviewed by one member of a panel of expert pathologists (panel experts) and by a second panel expert in case of disagreement on dysplasia grade. Agreement between two of three pathologists was established as the final diagnosis. Analysis was performed by kappa statistics. Due to absence of intestinal metaplasia, 127/920 (14%) patients were excluded. The interobserver agreement for dysplasia [no dysplasia (ND) versus indefinite for dysplasia/low-grade dysplasia (IND/LGD) versus high-grade dysplasia (HGD)/adenocarcinoma (AC)] between non-experts and first panel experts and between initial experts and first panel experts was fair (kappa = 0.24 and kappa = 0.27, respectively), and substantial for differentiation of HGD/AC from ND/IND/LGD (kappa = 0.62 and kappa = 0.58, respectively). There was considerable interobserver variability in the interpretation of ND or IND/LGD in BO between non-experts and experts, but also between expert pathologists. This suggests that less subjective markers are needed to determine the risk of developing AC in BO.

Efficient automated assessment of genetic abnormalities detected by fluorescence in situ hybridization on brush cytology in a Barrett esophagus surveillance population

Automated assessment of genetic abnormalities detected by fluorescence in situ hybridization (FISH) in brush cytology specimens from patients with Barrett esophagus (BE) may enhance the clinical applicability of this methodology. The objectives of this study were to validate a novel, automated, proprietary system (CytoVison SPOT AX) for the assessment of FISH abnormalities in BE brush cytology and, subsequently, to use this automated method for screening of a BE surveillance cohort. FISH with DNA probes for chromosomes 9, 17, and Y, and for the 9p21 (p16), 17q11.2 (Her2/neu), and 17p13.1 (p53) loci was applied on brush cytology specimens from a surveillance cohort of 151 patients with BE. Validation of the automated system was performed by comparison of the automated FISH results with manual scores for the first 60 patients. There was 98% concordance between manual and automated FISH analysis with kappa values from 0.49 to 1 for the different probes. The loss of 17p13.1 (p53) was observed in only 5% of patients with no dysplasia (ND) and in 9% of patients with low-grade dysplasia (LGD) but increased to 46% in patients with high-grade dysplasia (HGD) (P < .005; Fisher exact test). Chromosomes 9 and 17 were observed in 6% of patients with ND, in 21% of patients with LGD, and in 62% of patients with HGD (P < .05). Ten percent of patients with ND had loss of the Y chromosome, which increased to 27% in patients with HGD (P< .05). The amplification of 17q11.2 (Her2/neu) was detected in 62% of patients with HGD (P < .001). The current investigation indicated that the CytoVison SPOT AX is an objective, efficient system for the analysis of DNA-FISH on BE brush cytology and is applicable for analyzing large populations of BE patients. In the current study cohort, the loss of 17p13.1 (p53), Y chromosome loss, and polysomy of chromosomes 17 and 9 were correlated with increasing grade of dysplasia in patients with BE.

Surveillance History of Barrett's Esophagus Patients Endoscopically Treated for Early Neoplasia

Background & Aims: Pts with Barrett's Esophagus (BE) undergo regular endoscopic surveillance aimed at early detection of esophageal adenocarcinoma. The cost-effectiveness of this, however, is debated. Aim of this study was to retrospectively evaluate the surveillance history of BE pts with endoscopically treated early neoplasia in order to make recommendations regarding surveillance intervals. Patients & Methods: BE pts who received primary endoscopic treatment between 1998 and 2005 for early cancer (EC) or high-grade intraepithelial neoplasia (HGIN) in a lesion or mass were included. Endoscopy and histology records were reviewed and the number of biopsies obtained was expressed as a percentage of the number that should have been taken according to the Seattle protocol. Results: 78 pts (64 ♂, median age 63 yrs (IQR 57-73)), 21 treated for HGIN, 57 for EC were included. In 32 (41%) pts the HGIN/EC was diagnosed at the initial endoscopy. The remaining 46 (59%) pts had a surveillance history prior to diagnosis of HGIN/EC with a median duration of 6.4 yrs (IQR 2.5-9.9). Eighty percent of these pts had LGIN diagnosed at least once during their surveillance period. These pts underwent a mean number of 5 (SD 2.7) endoscopies with mean 59% (SD 35.6) biopsies taken. Nine pts had no dysplasia (ND) diagnosed during prior surveillance endoscopies. Six of nine pts had undergone only one surveillance endoscopy and the median number of biopsies taken was 30% (IQR 20-49), significantly less than the number taken in the pts with LGIN (p = 0.004). Modeling showed that with annual surveillance in case of LGIN and a 5-year surveillance interval after 2 consecutive endoscopies with ND, all pts in this cohort still would have been detected. Conclusions: In this selected cohort of BE patients more than 40% of patients with HGIN/EC was identified at the first endoscopy, without any prior surveillance. Of the patients with a BE surveillance history, 80% had shown LGIN at least at one endoscopy prior to the diagnosis of HGIN/EC. Only few pts with HGIN/EC had no dysplasia detected during prior surveillance, which in general encompassed only one or two insufficiently performed endoscopies. These data may suggest that Barrett's surveillance with an annual interval in case of LGIN and a 5 year interval in case of 2 consecutive ND diagnoses is sufficient. This research was financially supported by AstraZeneca BV The Netherlands.

Preliminary Results of BÂRRX Ablation Trial in Patients with Non-Dysplastic Intestinal Metaplasia Versus Low Or High Grade Dysplasia

Aims: Assess the response associated with BÂRRX ablation of Barrett's esophagus (BE) in patients with no dysplasia (ND) vs low grade dysplasia (LGD) or high grade dysplasia (HGD), as well as short segment (SSBE, <3 cm) vs long segment (LSBE, >3 cm). Methods: Prospective trial in patients with BE confirmed by bx on prior EGD. Patients receive 2 ablations at 10 J/cm2 in the ND group or 12 J/cm2 in the LGD group during each treatment. Tolerability is recorded using a 7-day, 10-pt scale patient symptom diary.